Cilioplasm is a cellular compartment for calcium signaling in response to mechanical and chemical stimuli

Primary cilia with a diameter of ~200 nm have been implicated in development and disease. Calcium signaling within a primary cilium has never been directly visualized and has therefore remained a speculation. Fluid-shear stress and dopamine receptor type-5 (DR5) agonist are among the few stimuli that require cilia for intracellular calcium signal transduction. However, it is not known if these stimuli initiate calcium signaling within the cilium or if the calcium signal originates in the cytoplasm. Using an integrated single-cell imaging technique, we demonstrate for the first time that calcium signaling triggered by fluid-shear stress initiates in the primary cilium and can be distinguished from the subsequent cytosolic calcium response through the ryanodine receptor. Importantly, this flow-induced calcium signaling depends on the ciliary polycystin-2 calcium channel. While DR5-specific agonist induces calcium signaling mainly in the cilioplasm via ciliary CaV1.2, thrombin specifically induces cytosolic calcium signaling through the IP₃ receptor. Furthermore, a non-specific calcium ionophore triggers both ciliary and cytosolic calcium responses. We suggest that cilia not only act as sensory organelles but also function as calcium signaling compartments. Cilium-dependent signaling can spread to the cytoplasm or be contained within the cilioplasm. Our study thus provides the first model to understand signaling within the cilioplasm of a living cell.     

Activation of the AXL kinase causes resistance to EGFR-targeted therapy in lung cancer

Human non-small cell lung cancers (NSCLCs) with activating mutations in EGFR frequently respond to treatment with EGFR-targeted tyrosine kinase inhibitors (TKIs), such as erlotinib, but responses are not durable, as tumors acquire resistance. Secondary mutations in EGFR (such as T790M) or upregulation of the MET kinase are found in over 50% of resistant tumors. Here, we report increased activation of AXL and evidence for epithelial-to-mesenchymal transition (EMT) in multiple in vitro and in vivo EGFR-mutant lung cancer models with acquired resistance to erlotinib in the absence of the EGFR p.Thr790Met alteration or MET activation. Genetic or pharmacological inhibition of AXL restored sensitivity to erlotinib in these tumor models. Increased expression of AXL and, in some cases, of its ligand GAS6 was found in EGFR-mutant lung cancers obtained from individuals with acquired resistance to TKIs. These data identify AXL as a promising therapeutic target whose inhibition could prevent or overcome acquired resistance to EGFR TKIs in individuals with EGFR-mutant lung cancer.     

A genome-wide association study in Han Chinese identifies new susceptibility loci for ankylosing spondylitis

To identify susceptibility loci for ankylosing spondylitis, we performed a two-stage genome-wide association study in Han Chinese. In the discovery stage, we analyzed 1,356,350 autosomal SNPs in 1,837 individuals with ankylosing spondylitis and 4,231 controls; in the validation stage, we analyzed 30 suggestive SNPs in an additional 2,100 affected individuals and 3,496 controls. We identified two new susceptibility loci between EDIL3 and HAPLN1 at 5q14.3 (rs4552569; P = 8.77 × 10(-10)) and within ANO6 at 12q12 (rs17095830; P = 1.63 × 10(-8)). We also confirmed previously reported associations in Europeans within the major histocompatibility complex (MHC) region (top SNP, rs13202464; P < 5 × 10(-324)) and at 2p15 (rs10865331; P = 1.98 × 10(-8)). We show that rs13202464 within the MHC region mainly represents the risk effect of HLA-B*27 variants (including HLA-B*2704, HLA-B*2705 and HLA-B*2715) in Chinese. The two newly discovered loci implicate genes related to bone formation and cartilage development, suggesting their potential involvement in the etiology of ankylosing spondylitis.     

Genome-wide association study identifies susceptibility loci for open angle glaucoma at TMCO1 and CDKN2B-AS1

We report a genome-wide association study for open-angle glaucoma (OAG) blindness using a discovery cohort of 590 individuals with severe visual field loss (cases) and 3,956 controls. We identified associated loci at TMCO1 (rs4656461[G] odds ratio (OR) = 1.68, P = 6.1 × 10(-10)) and CDKN2B-AS1 (rs4977756[A] OR = 1.50, P = 4.7 × 10(-9)). We replicated these associations in an independent cohort of cases with advanced OAG (rs4656461 P = 0.010; rs4977756 P = 0.042) and two additional cohorts of less severe OAG (rs4656461 combined discovery and replication P = 6.00 × 10(-14), OR = 1.51, 95% CI 1.35-1.68; rs4977756 combined P = 1.35 × 10(-14), OR = 1.39, 95% CI 1.28-1.51). We show retinal expression of genes at both loci in human ocular tissues. We also show that CDKN2A and CDKN2B are upregulated in the retina of a rat model of glaucoma.     

耗能连梁采用新型复合阻尼器后对剪力墙结构性能的影响

研究一种震后可替换的新型复合阻尼器置于连梁跨中以实现保护连梁并提高连梁耗能能力的目标.在ABAQUS有限元软件平台上根据复合阻尼器的特点提出一种可以有效反映其特征的等效简化模型,并与仿真模型进行对比验证;将等效简化模型应用于高层剪力墙结构的连梁中,进行罕遇地震下的剪力墙结构动力时程分析;以混凝土连梁为参照,研究安装了复...     

关于卡方复形的强shellable性质

研究了卡方复形上的与强shellable相关的一些性质,证明了对任意一个复形Δ,若x是使基础集上每个点都染不同颜色的一个染色,那么Δx是一个强shellable复形;若Δ是一个TA复形,那么对Δ的任意一个染色x,Δx是一个强shellable复形;复形Δ在任意一个染色x下的卡方复形Δx是matroid的当且仅当Δ是一个...     

针对要点防空模型的作战兵力优化研究

为了在现代化联合防空作战中,根据蓝方火力配置,红方能够做出最优的兵力分配,使防空效能最大化。从要点防空的任务角度出发,对作战兵力分配进行建模优化,并对优化后的兵力分配效能进行评估。首先选定任务背景为近海小规模局部战争,对复杂作战情况进行抽象得到模型。对模型进行优化,求解得到红方最优兵力分配结果,提出一种新方法,简化了对有限制的类二项分布期望的求解,得到蓝方各类进攻力量成功突防的期望以及红方要点平均损耗期望,并用此值定量评估联合防空的兵力分配效能。最后,进行了实例分析,验证了模型的有效性。     

Extraction of Signal Frequency in Laser Ranging of Space Target Based on FPGA

Aiming at the problems in a linear frequency modulation continuous wave(LFMCW) ranging lidar system, such as low signal-to-noise in echo beat frequency and difficult extraction of the signal frequency, a method with high-speed and high accuracy based on field programmable gate array(FPGA) is proposed. Firstly, the laser echo beat signal is sampled by high-speed analog to digital converter(ADC) and then processed in FPGA for data preprocessing. After the signal is processed by the 8 192-point FPGA will obtain the frequency spectrum and then apply the frequency spectrum to data processing and adaptive noise signal peak detection. These two steps realize the real-time and accurate extraction process of the target echo beat signal frequency. Finally, the spectrum data is transmitted to the host computer and processed through the external data acquisition board for real-time spectrum display. Experimental results show that data preprocessing and spectrum data processing can effectively suppress DC bias and system modulation noise. Adaptive noise peak detection can accurately divide the threshold contour according to the dynamic noise of the system and realize the detection of target signal peak. When the sampling clock of the system is 100 MHz, the time needed for each calculation of the spectrum is 81.92 μs, and the refresh rate of the spectrum reaches 12.2 kHz, which meets the real-time requirements of the system.     

电刺激小脑顶核对大鼠心肌梗死后心脏神经再生的影响

探讨预先电刺激小脑顶核(FNS)对大鼠心肌梗死(MI)后心脏神经再生的干预作用。将90只Wistar大鼠随机分为:①MI组,结扎左冠状动脉前降支(LAD);②预先电刺激小脑顶核后再予以LAD结扎组(FNS MI组);③毁损小脑顶核后电刺激该部位,再行LAD结扎组(FNL FNS MI组)。各组又分MI后1,7,21d3个时间点。另设假手术组(Sham组)。应用免疫组织化学方法显示心脏组织胆碱乙酰转移酶(CHAT)和酪氨酸羟化酶(TH)。检测各时间点梗死区与非梗死区TH、CHAT阳性神经纤维分布密度,MI组与Sham组相比显著减少(P<0.01);FNS MI组较MI组显著增多(P<0.05);FNL FNS MI组与MI组比较无显著性差异(P>0.05)。因此,电刺激小脑顶核可增加梗死区和非梗死区心肌组织TH、CHAT染色阳性神经纤维密度,促进MI后心脏神经纤维再生。     

Micro-expression recognition algorithm based on the combination of spatial and temporal domains

Aiming at the problem of unsatisfactory effects of traditional micro-expression recognition algorithms,an efficient micro-expression recognition algorithm is proposed,which uses convolutional neural networks(CNN) to extract spatial features of micro-expressions,and long short-term memory network(LSTM) to extract time domain features.CNN and LSTM are combined as the basis of micro-expression recognition.In many CNN structures,the visual geometry group(VGG) using a small convolution kernel is finally selected as the pre-network through comparison.Due to the difficulty of deep learning training and over-fitting,the dropout method and batch normalization method are used to solve the problem in the VGG network.Two data sets CASME and CASME II are used for test comparison,in order to solve the problem of insufficient data sets,randomly determine the starting frame,and a fixedlength frame sequence is used as the standard,and repeatedly read all sample frames of the entire data set to achieve trayersal and data amplification.Finallv.a hieh recognition rate of 67.48% is achieved.